Highlights from Recent Cancer Literature
Journal: Cancer Research (2015)

Huang and colleagues identify voltage-gated potassium channel EAG2 (KCNH5) as regulating cell volume dynamics and tumor growth in medulloblastoma. EAG2 expression was increased in a WNT, SHH, and group 4 human medulloblastoma. Knockdown reduced medulloblastoma growth and prolonged survival in xenografts. Cells with EAG2 knockdown underwent mitotic catastrophe with failure of premitotic cytoplasmic condensation and G2 cell cycle arrest. Although arrest was independent of p53, DNA damage checkpoint, or AKT signaling, inhibition of the p38 pathway rescued the G2 arrest and growth defects conferred by EAG2 knockdown. In addition, overexpression of membrane EAG2 at interphase resulted in reduced cell volumes. Thus, EAG2 represents a novel therapeutic target, as it may help control progression through G2 and mitotic entry in medulloblastoma.Huang X, He Y, Dubuc AM, Hashizume R, Zhang W, Reimand J, et al. EAG2 potassium channel with evolutionarily conserved function as a brain tumor target. Nat Neurosci 2015;18:1236–46.RING finger protein 43 (RNF43) is an E3 ubiquitin ligase that negatively regulates WNT signaling. Loregger and colleagues localized endogenous RNF43 in both gastrointestinal and tumorous cells and tissue. Endogenous RNF43 was enriched in the nucleus, where it attenuated the activity of the WNT dependent transcription factor TCF4 by sequestering it to the nuclear membrane. This effect on TCF4 did not require its ubiquitination and did not regulate TCF4 protein levels. Mutant forms of RNF43 identified in gastrointestinal tumors were unable to sequester TCF4 and exhibited constitutive WNT activity. High levels of RNF43 expression were also associated with poor outcome in stage II colorectal cancer. Consistent with RNF43 being driven by WNT activity in these cancers, β-catenin and TCF4 colocalized at this locus near several TCF4 binding sites.Loregger A, Grandl M, Mejías-Luque R, Allqäuer M, Degenhart K, Haselmann V, et al. The E3 ligase RNF43 inhibits WNT signaling downstream of mutated β-catenin by sequestering TCF4 to the nuclear membrane. Sci Signal 2015;8:ra90. doi: 10.1126/scisignal.aac6757.Mody and colleagues studied germline and tumor DNA from 102 children and young adults (with relapsed/refractory liquid and solid tumors represented) over 2.5 years, integrating genomic and transcriptomic sequencing to detect potentially actionable molecular findings (PAF). Forty-six percent of cases with sequencing results had a PAF, and that action was taken in 54% of patients. Actions included a change in therapy or identification of a germline mutation deemed clinically relevant for genetic counseling. The response data in the patients who underwent a change in treatment are early and the authors are appropriately cautious in drawing conclusions about objective benefit derived. This study highlights several key topics, including clonal, drug, and ethical evolution, that will need to be tackled moving forward in this era of precision medicine.Mody RJ, Wu YM, Lonigro RJ, Cao X, Roychowdhury S, Vats P, et al. Integrative clinical sequencing in the management of refractory or relapsed cancer in youth. JAMA 2015;314:913–25.Kim and colleagues (1) investigated 38 pairs of primary and recurrent glioblastoma (GBM) tumors, 33 comprised of treatment naïve, IDH1 wild-type GBM and paired recurrent tumors following standard of care therapy. Comparison of validated mutations in initial and recurrent tumor pairs with matched normal tissue revealed mutation retention ratio ranging from 11% to 97%. Comparing tumors with low versus high mutation retention ratios (branched versus linear evolution) revealed a correlation between the mutation retention ratio and distance of recurrence from the initial tumor. These data in combination with data from Mazor and colleagues (2) detailing the codependency of genetic and epigenetic events in low-grade glioma evolution demonstrate the dynamic spatiotemporal evolution of glioma. Understanding tumor evolution and predicting alterations promise to improve therapeutic strategies.1. Kim J, Lee IH, Cho HJ, Park CK, Jung YS, Kim Y, et al. Spatiotemporal evolution of the primary glioblastoma genome. Cancer Cell 2015;28:318–28.2. Mazor T, Pankov A, Johnson BE, Hong C, Hamilton EG, Bell RJ, et al. DNA methylation and somatic mutations converge on the cell cycle and define similar evolutionary histories in brain tumors. Cancer Cell 2015;28:307–17.Wright and colleagues utilized transgenic mouse models of breast cancer to determine relationships between oncogenic pathway activation and breast cancer subtypes by activating the PI3K, STAT3, and RAS signaling pathways singly and in pairs. All three oncogenes cooperated during primary tumor formation, with dissemination dependent on RAS. RAS-induced adenocarcinomas showed transcriptional profiles similar to human basal-like and HER2+ tumors. When RAS was combined with PIK3CAH1047R, an oncogenic mutant linked to estrogen receptor α positive (ERα+)/luminal breast cancer, metastatic luminal B-like tumors developed. In patient samples, RAS activation correlated with reduced survival in ERα+ disease independently of PI3K or STAT3 activation. These results suggest RAS as central to tumor dissemination and poor prognosis for ERα+/luminal breast cancer, suggesting hormone therapy supplemented with MAPK-pathway targeted agents as a possible treatment.Wright KL, Adams JR, Liu JC, Loch AJ, Wong RG, Jo CE, et al. Ras signaling is a key determinant of metastatic dissemination and poor survival of luminal breast cancer patients. Cancer Res 2015; Published OnlineFirst September 23, 2015; doi:10.1158/0008-5472.CAN-14-2992.In Drosophila, the numbers of each cell type in developing structures are determined in part by cell competition, where slow-dividing cells (“losers”) are eliminated by fast-dividing cells (“winners”). Cells with higher levels of myc selectively expand at the expense of adjacent cells with lower levels. Levayer and colleagues used long-term live cell imaging of the pupal notum and wing imaginal disc coupled with quantification of direct surface contact between winner-winner, winner-loser, and loser-loser cells interfaces. Myc induced the elimination of loser clones by preferentially promoting winner-loser cell intercalation through modulation of F-actin levels between winner and loser junctions. Differences in F-actin levels between winners and losers were in turn regulated by PIP3 second messenger pathways. This study details how myc directly promotes reorganization of tissue structures akin to invasion and destruction of normal tissue by cancer cells.Levayer R, Hauert B, Moreno E. Cell mixing induced by myc is required for competitive tissue invasion and destruction. Nature 2015;524:476–80.Note: Breaking Advances are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.